TITLE: GMP Synthesis of a Tau Oligomer Inhibitor to Enable Clinical Development for ADRD PROJECT SUMMARY - SBIR Funding Opportunity: NIA PAS-18-187, Advancing Research on Alzheimer's Disease (AD) & AD-Related Dementias (ADRD) (R43/R44 Clinical Trial Optional) The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer?s disease (AD) and related dementias (ADRD). There is a critical unmet need for a disease modifying drug for AD. Chronic treatment strategies require economically feasible approaches such as small molecule drugs. This program is progressing to fill this need with a disease modifying drug that, if successful, will have a tremendous impact on the more than 5.8 million Americans who currently have AD (projected to be 14 million by 2050) and their caregivers, and will help reduce the current cost of $290 billion (projected to be $1.1 trillion by 2050) to our nation. Our small molecule leads target tau self-association into oligomers for neurodegeneration. Tau protein?s normal function is to stabilize microtubules thereby enabling synaptic function. Tau oligomers are the acutely toxic species of tau and their reduction will modify the course of AD. Our in vivo efficacy studies were carried out blindly and independently by Peter Davies, Ph.D., a key opinion leader in the tau targeting field. The lead compound inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD using a preventive paradigm. These results demonstrate that our lead compound reduced self-association of tau and inhibited formation of insoluble tau aggregates. The activity translated from in vitro and cellular assays to an in vivo model of tau aggregation validating our screening approach and showing that targeting oligomer formation can inhibit the entire tau aggregation pathway. Furthermore, preliminary safety testing showed a good profile in terms of MTD, Ames, hERG, 14 day dose range finding study, and safety pharmacology. This application is for the cGMP manufacture of 2 - 3 kilograms of our lead (TO-0582AQ) for use in clinical development. Further, we will develop the IND package for FDA that will be supported by the GLP safety studies that are presently being carried out under a parallel NIH funded program (AG062021). We will also perform pre-formulation work under the proposed program and will qualify activity of API, formulated API and any intermediates using our proprietary in-vitro screening assays. Additional activities to be taken include managing all subcontractors and consultants and responsibility for all reporting requirements to NH for the proposed program. Our collaborators include Edward Cheesman, Ph.D., Chemistry and Manufacturing Controls Consultant who managed our scale up for the non-clinical safety studies, will also help oversee the GMP scale-up of our lead compound for clinical development. Pre-formulation work will be carried out by Rajaram Vaidyanathan, RPh, Ph.D., at Gram Laboratories, Inc. Timothy J. Kachmar, M.S., McCormick LifeSciences, LLC will be our regulatory consultant.